Controversy

The case for Helicobacter pylori eradication in India: sensationalism, skepticism and scientific salesmanship
Vineet Ahuja Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029

ith tenacity and a prepared mind the duo challenged prevailing dogmas, said a press release from the Nobel Assembly at Karolinska Institute in Stockholm, Sweden announcing that the 2005 Nobel prize in Physiology or Medicine had been awarded to Robin Warren and Barry Marshall for their discovery that a bacterium named Helicobacter pylori causes most peptic ulcers. 1,2 It is somewhat discomforting that this Journal has commissioned a debate on the need for treating H. pylori infection at a time when triumph of the ulcer-bug theory formed news of the week for many journals and even the lay press. It thus appears unjust to wield, or at least an inopportune time for wielding, a coroners scalpel to exhume the odyssey. Why are we still reluctant to embrace this concept? Was it an unbridled sensationalism for over a decade that has spurred a rebound vociferous skepticism? In the year 2006, a debate on the proficiency of H. pylori eradication would be classified as an unfair duel. Not the David vs. Goliath kind where the underdog wins but a duel where the result is not merely a writing on the wall but is deeply etched and engraved. Nevertheless, it provides a good opportunity to place on record the evidence that has led to the acceptance of H. pylori eradication as treatment for peptic ulcer disease. In pursuit of this objective, this article will focus on four central concepts: i) Is there irrefutable evidence that H. pylori causes peptic ulcer and gastric cancer? ii) Does eradication of H. pylori infection alter the natural history of these diseases? iii) Has the beneficial effect been exaggerated? and, iv) What are the diseases in which benefit of H. pylori eradication remains unproven? Evidence that H. pylori causes peptic ulcer and gastric cancer

Peptic ulcer H. pylori infection has a strong association with chronic active gastritis and duodenal ulcer (DU). Ingestion of H. pylori has been shown to produce acute antral gastritis.3,4,5 H. pylori infection can be detected in 90% of patients with DU and 70% of those with gastric ulcers. 6 A critique published in 1991 deterCopyright 2006 by Indian Society of Gastroenterology

mined that there was strong association between H. pylori and DU, but that evidence for biological gradient and temporality and supportive experimental evidence was insufficient. 7 Since then, plenty of new evidence has become available. Sipponen et al showed that 11% of individuals with H. pylori infection developed DU over a 10year follow up, in contrast to fewer than 1% of noninfected individuals.8 Cullen et al studied 407 subjects and showed that DU developed in 15% of H. pyloriseropositive individuals as compared to 3% of seronegative individuals.9 In a Scandinavian followup study over 10 years, 13% of patients with H. pylori gastritis developed peptic ulcer. 10 Kochs first postulate states that the organism must always be found in the diseased animals and not in healthy ones. Only 15%-20% of H. pylori infected persons develop peptic ulcer disease. However, the role of indigenous biota in human diseases is often complex. For instance, Candida albicans and Bacteroides spp. are normally present in humans and yet can at times cause life-threatening disease. 11 Kochs second postulate states that the organism must be isolated from diseased animals and grown in pure culture away from the animal. This postulate was fulfilled by Marshall who succeeded in culturing H. pylori, after 34 failures. 12 Kochs third postulate requires that the organism isolated in pure culture must initiate and reproduce the disease when re-inoculated into susceptible animals, and the fourth states that the organism should be re-isolated from the experimentally infected animals. Ohkusa et al experimentally inoculated Mongolian gerbils with three strains of H. pylori; all three strains induced gastric ulceration and two strains, in addition, induced gastric metaplasia in the duodenum and duodenitis.13 Two gerbils developed superficial duodenal ulceration; this occurred on a background of gastric metaplasia, as in humans. The next step is a biologically and conceptually satisfying pathogenetic mechanism for production of DU by H. pylori infection; this, however, is yet to be attained. It has been proposed that the outcome of H. pylori infection may depend on the gastric

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Ahuja acid secretory ability of the infected individual; thus, persons with naturally high acid secretion are prone to develop antrum-predominant gastritis and are at increased risk of DU, whereas those with low acid secretion develop colonization of gastric body with H. pylori, leading to multifocal atrophic gastritis and possibly gastric cancer. 14

H. pylori eradication in India: the case for gastric microecology related to improved nutrition, changes in nature of H. pylori colonization, and in immune response to the organism related to older age at the time of acquisition of infection. Also, differences in response of individual hosts, in strains of H. pylori, in environmental factors, and in age of the patient at the time of acquisition of the infection may determine the variable response to infection. Eradication of H. pylori infection and natural history of peptic ulcer disease The most persuasive argument in support of a pathogenic role for H. pylori in peptic ulcer disease relates to a dramatic decrease of spontaneous relapse rate of DU after successful eradication of infection with this organism. 23 Hopkins et al reviewed 14 studies on DU and eight on gastric ulcer and found that ulcer recurrence was significantly less common among patients with cured H. pylori infection (6% vs. 67% for DU, 4% vs. 59% for gastric ulcers). 24 This reduction is sustained for at least seven years following H. pylori eradication. Eradication of H. pylori also reduces the rate of recurrence of ulcer hemorrhage more effectively than does long-term maintenance treatment with either ranitidine or omeprazole. 25 The overwhelming reduction in ulcer recurrence rates after H. pylori eradication has made this a standard treatment for patients with peptic ulcer disease. However, epidemiological differences may restrict a simple extrapolation of these data from developed countries to developing countries. Due to a high frequency of infection, overcrowding and lower standards of hygiene, the H. pylori re-infection rate after treatment may be higher in the latter countries. This, combined with lower eradication rates, may partially nullify the long-term benefits of H. pylori eradication on the natural history of peptic ulcer disease in developing countries. 26 However, does this mean that we stop attempts at eradicating H. pylori infection, or should we devise more effective strategies to treat this infection and prevent re-infection? For instance, if drug resistance were frequent among patients with tuberculosis and treatment delivered poor results, would we look for alternative etiologies for such patients or rather develop more effective treatment strategies? Has the beneficial effect been exaggerated? The arguments that H. pylori may not be the primary cause of DU are as follows: prevalence of H. pylorinegative DU is increasing; early cases of DU are

Gastric cancer Gastric carcinogenesis is a multi-step process, the key steps being chronic superficial gastritis, chronic atrophic gastritis leading to achlorhydria, intestinal metaplasia and dysplasia. An epidemiological association between H. pylori and gastric cancer was initially established in three prospective case-control studies and a cohort study, followed by a meta-analysis. 1518

Watanabe et al studied gastric histology in Mongolian gerbils that had been experimentally infected with H. pylori.20 At 26 weeks post-inoculation, all infected animals showed severe active chronic gastritis, ulcers and intestinal metaplasia. By 62 weeks, adenocarcinoma had developed in the pyloric region of 37% of the infected gerbils, fulfilling Kochs postulates for the relationship of H. pylori and gastric cancer. Further, in a follow up of 1526 Japanese patients, gastric cancer developed in 3% of H. pylori-infected patients but in none of the uninfected patients.21 H. pylori is also an important factor for gastric MALT lymphomas, although it is difficult to prove an association because of a low incidence of this disease.22 A few befuddling questions remain. Why do only 1% and 15% of infected people develop gastric cancer and peptic ulcer, respectively? Why is H. pylori infection most prevalent among the elderly whereas peptic ulcer is a disease of the young? Why has the incidence of DU gone up in the last century, while the prevalence of H. pylori was on the downslide? Attempts have been made to answer these questions. H. pylori has been a part of the gastric biota since antiquity. The ultra-low biological activity of its lipopolysaccharide and expression of Lewis antigens facilitate its persistence in human hosts. Changes in modern life are however gradually eliminating it from being only a commensal. Peptic ulcer disease was uncommon when H. pylori colonization was nearly universal. The incidence of peptic ulcer started rising, as in the last century, as the colonization rate of H. pylori began to decline. This increase in incidence of peptic ulcer could be related to changes in

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Ahuja more often H. pylori negative than chronic cases of DU; colonization of gastric metaplasia in duodenum with H. pylori is infrequent; and rate of recurrence of H. pylori infection is higher in developing countries. One needs to recognize that H. pylori, though an important cause of peptic ulcer, is not the only cause. Laines meta-analysis showed that the 20% recurrence rate of peptic ulcers after successful eradication of H. pylori infection may be because non-H. pylori, non-NSAID induced ulcers are more common than previously believed.27 Thus, ulcers in patients with H. pylori infection are not always H. pylori induced, since we are currently unable to differentiate virulent and commensal H. pylori. Presence of H. pylori anywhere does not imply that it should be treated instantaneously. Blaser has strongly argued that H. pylori forms normal biota of the human stomach and infection with it should be treated selectively. He believes that H. pylori infection is beneficial and protects humans against gastroesophageal reflux disease and cardia cancer.28 Hence, elimination of H. pylori infection is needed only in defined settings, as discussed above. The issue would become clearer when we have accurate and convenient tests to discriminate between virulent and non-virulent H. pylori, somewhat akin to the situation with Entamoeba dispar and E. histolytica.29 Disease associations where benefit of H. pylori eradication is still unproven

H. pylori eradication in India: the case for pylori in patients with GERD, 30 suggesting that H. pylori infection protected against GERD. Evidence for this protective role is three-fold: theoretical plausibility, negative epidemiological association, and cagA strains having an even greater negative association. To prove the protective role of H. pylori for GERD, we need to (i) determine the effect of H. pylori eradication on GERD outcomes (reflux esophagitis and heartburn) in patients with DU, and (ii) determine the effect of H. pylori infection on reflux esophagitis. Data are available from 13 trials in patients with DU, which estimated proportion of patients newly developing reflux esophagitis following H. pylori eradication therapy. 31 These show that H. pylori eradication status had no effect on rates of persistence of pre-existing GERD or fresh development of GERD. This is not surprising because patients with DU have high acid secretion, which decreases following H. pylori eradication. It follows that the likelihood of their developing GERD should decrease, not increase, after H. pylori eradication. The next issue is the effect of H. pylori infection and eradication in patients with GERD. A prospective, double-blind study failed to find any difference in the severity of GERD between patients with and without H. pylori infection. 32 Three randomized controlled trials have looked at the effect of H. pylori eradication in patients with reflux esophagitis and found no worsening of symptoms or of acid reflux. 33,34,35 Moayyaedi et al concluded that treatment of H. pylori gastritis in healthy population did not lead to symptoms of GERD over a 2-year period. 36 Hence, negative epidemiological association between H. pylori infection and GERD is not supported by clinical data, and H. pylori eradication does not induce or worsen GERD, either in patients with DU or preexisting GERD or in the healthy population. The last issue is whether patients receiving longterm PPI therapy for the treatment of GERD require prior H. pylori eradication. Administration of PPI to H. pylori-infected subjects induces a corpuspredominant gastritis, a recognized risk factor for gastric cancer; yet we do not know whether such corpus atrophic gastritis progresses with time. Also, eradication of H. pylori infection may reduce the efficacy of PPI in controlling GERD since PPI therapy has been shown to be much more potent in H. pyloripositive subjects. However, since eradication of H. pylori infection does not worsen GERD in patients with both DU and GERD, it is unlikely to harm patients with GERD alone. Thus, treatment may be used in patients who are candidates for long-term

Gastroesophageal reflux disease (GERD) The issues that require examination are: (i) Is there an epidemiological association between GERD and H. pylori? (ii) How does eradication of H. pylori infection affect GERD in patients with DU or reflux esophagitis, and in the healthy population? and, (iii) Does one need to eradicate H. pylori infection if long-term proton pump inhibitor (PPI) therapy is planned for GERD treatment? It is not merely the presence of H. pylori but its density and distribution in the stomach that determine gastric acid secretion, and hence the impact of this infection on GERD. Thus, antral colonization with H. pylori is associated with increased gastric acid secretion and increased propensity to develop GERD. On the other hand, colonization of the gastric corpus is associated with reduced gastric secretion and may protect against GERD. Thus, both a direct and an inverse association between H. pylori and GERD are theoretically plausible. Raghunath et al examined 20 studies and obtained a pooled odds ratio of 0.60 (95% CI 0.47-0.78) for the presence of H.

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Ahuja PPI therapy, though there is no conclusive proof yet in favor of this approach.

H. pylori eradication in India: the case for

Attempt to fulfill Kochs postulates for pyloric Campylobacter. Med J Aust 1985;142:436-9. 4. Morris A, Nicholson G. Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. Am J Gastroenterol 1987;82:192-9. 5. Graham Y, Alpert LC, Smith JL, Yoshimura HH. Iatrogenic Campylobacter pylori infection as a cause of epidemic achlorhydria. Am J Gastroenterol 1988;83:974-80. 6. Malaty HM, Nyren O. Epidemiology of Helicobacter pylori infection. Helicobacter 2003;8(Suppl 1):8-12. 7. Rabeneck L, Ransohoff DF. Is Helicobacter pylori a cause of duodenal ulcer? A methodologic critique of current evidence. Am J Med 1991;91:566-72. 8. Sipponen P, Varis K, Fraki O, Korri UM, Seppala K, Siurala M. Cumulative 10-year risk of symptomatic duodenal and gastric ulcer in patients with or without chronic gastritis. A clinical follow-up study of 454 outpatients. Scand J Gastroenterol 1990;25:966-73. 9. Cullen DJE, Collins BJ, Christiansen KJ, Epis J, Warren JR, Cullen KJ. Long term risk of peptic ulcer disease in people with Helicobacter pylori infection: a community based study (Abstract). Gut 1993;34(Suppl 1):F284 10. Niemela S, Karttunen T, Kerola T. Helicobacter pyloriassociated gastritis. Evolution of histologic changes over 10 years. Scand J Gastroenterol 1995;30:542-9. 11. Blaser MJ. Helicobacters are indigenous to the human stomach: duodenal ulceration is due to changes in gastric microecology in the modern era. Gut 1998;43:721-7. 12. Fukuda Y, Shimoyama T, Shimoyama T, Marshall BJ. Ksai, Kobayashi and Kochs postulates in the history of Helicobacter pylori. In: Marshall BJ, Ed. Helicobacter Pioneers. Blackwell Science, Victoria. 2002: p. 15-24. 13. Ohkusa T, Okayasu I, Miwa H, Ohtaka K, Endo S, Sato N. Helicobacter pylori infection induces duodenitis and superficial duodenal ulcer in Mongolian gerbils. Gut 2003;52:797803. 14. Graham DY. Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric cancer: a model. Gastroenterology 1997;113:1983-91. 15. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991;325:1127-31. 16. Nomura A, Stemmermann GN, Chyou P-H, Kato I, PerezPerez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 1991;325:1132-6. 17. Forman D, Newell DG, Fullerton F, Yarnell JW, Stacey AR, Wald N, et al. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. Br Med J 1991;302:1302-5. 18. The Eurogast Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet 1993;341:1359-62. 19. Huang J-Q, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998;114:1169-79. 20. Watanabe T, Tada M, Nagai H, Sasaki S, Nakao M. Helicobacter pylori infection induces gastric cancer in Mongolian gerbils. Gastroenterology 1998;115:642-8.

Functional dyspepsia Several clinical trials have studied the role of H. pylori infection in non-ulcer dyspepsia (NUD). However, six well-designed large studies reached contradictory conclusions, 37-42 suggesting that functional dyspepsia was a heterogeneous disorder. Similarly, five meta-analyses on the subject have shown conflicting results. 43-48 Interestingly, Laine et al 44 concluded that symptom relief after H. pylori eradication therapy was no better than with a placebo, whereas a Cochrane systematic review showed a 9% (95% CI 4-14) relative risk reduction after H. pylori eradication.49 This lack of consistency suggests that eradication of H. pylori infection may be useful in a small subset of patients with NUD. However, this argument may not be applicable globally. In particular, there are no Indian data to either support or refute a role for eradication of H. pylori infection in patients with NUD. Thus, it appears impractical to provide H. pylori eradication therapy to a huge number of H. pylori-infected persons with NUD till further data on the predictors of response to such treatment are available.
Conclusions It is evident that H. pylori infection has a causal link with peptic ulcer and gastric cancer and that its successful eradication dramatically reduces the risk of ulcer recurrence. Therefore, an attempt at eradication of this infection should be the first-line approach for all patients with H. pylori-associated peptic ulcer disease. It is quite apparent that much of the skepticism about the bug-ulcer relationship was spurred by the initial sensationalism, the exaggerated attention that H. pylori received soon after its discovery, and the unsubstantiated early revelry for claims of curing the disease. It is however now time to shed this skepticism and move on to embrace the scientific evidence supporting the relationship. Perhaps, George Bernard Shaws words sum it all well: All great truths begin as blasphemies. References
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Ahuja
21. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:7849. 22. Andersen LP, Nielsen H. Peptic ulcer: an infectious disease? Ann Med 1993;25:563-8. 23. Penston JG. Helicobacter pylori eradication: understandable caution but no excuse for inertia. Aliment Pharmacol Therap 1994;8:369-89. 24. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-52. 25. Gisbert JP, Khorrami S, Carballo F, Calvet X, Gene E, Dominguez-Munoz JE. H. pylori eradication therapy vs. antisecretory non-eradication therapy (with or without longterm maintenance antisecretory therapy) for the prevention of recurrent bleeding from peptic ulcer. Cochrane Database Syst Rev 2004;(2):CD004062. 26. Ahuja V, Sharma MP. High recurrence rate of Helicobacter pylori infection in developing countries. Gastroenterology 2002;123:653-4. 27. Laine L, Hopkins RJ, Girardi LS. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the United States been overstated? A meta-analysis of rigorously designed trials. Am J Gastroenterol 1998;93:1409-15. 28. Blaser MJ. An endangered species in the stomach. Sci Am 2005;292:38-45. 29. Ahuja V. Gazing through the crystal ball: Helicobacter pylori. Trop Gastroenterol 2004;25:57-9. 30. Raghunath A, Hungin AP, Wooff D, Childs S. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. Br Med J 2003;326:737. 31. Raghunath AS, Hungin AP, Wooff D, Childs S. Systematic review: the effect of Helicobacter pylori and its eradication on gastro-oesophageal reflux disease in patients with duodenal ulcers or reflux oesophagitis. Aliment Pharmacol Ther 2004;20:733-44. 32. Fallone CA, Barkun AN, Mayrand S, Wakil G, Friedman G, Szilagyi A, et al. There is no difference in the disease severity of gastro-oesophageal reflux disease between patients infected and not infected with H. pylori. Aliment Pharmacol Ther 2004;20:761-8. 33. Moayyedi P, Bardhan C, Young L, Dixon MF, Brown L, Axon AT. Helicobacter pylori eradication does not exacerbate reflux symptoms in gastroesophageal reflux disease. Gastroenterology 2001;121:1120-6. 34. Schwizer W, Thumshirn M, Dent J, Guldenschuh I, Menne D, Cathomas G, et al. Helicobacter pylori and symptomatic relapse of gastro-oesophageal reflux disease: a randomised controlled trial. Lancet 2001;357:1738-42. 35. Tefera S, Hatlebakk JG, Berstad AE, Berstad A. Eradication of Helicobacter pylori does not increase acid reflux in patients with mild to moderate reflux oesophagitis. Scand J Gastroenterol 2002;37:877-83. 36. Moayyedi P, Feltbower R, Brown J, Mason S, Mason J, Nathan J, et al. Effect of population screening and treatment for Helicobacter pylori on dyspepsia and quality of

H. pylori eradication in India: the case for

life in the community: a randomised controlled trial. Leeds HELP Study Group. Lancet 2000;355:1665-9. 37. McQuaid KR. Eradication of Helicobacter pylori in nonulcer dyspepsia: how much analysis do we need? J Clin Gastroenterol 2003;36:291-4. 38. Talley NJ, Vakil N, Ballard ED II, Fennerty MB. Absence of benefit of eradicating Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med 1999;341:1106-11. 39. Talley NJ, Janssens J, Lauritsen K, Racz I, Bolling-Sternevald E. Eradication of Helicobacter pylori in functional dyspepsia: randomised double blind placebo controlled trial with 12 months follow up. The Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study Group. Br Med J 1999;318:833-7. 40. Blum AL, Talley NJ, OMorain C, van Zanten SV, Labenz J, Stolte M, et al. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect One Year after Treatment (OCAY) Study Group. N Engl J Med 1998;339:1875-81. 41. McColl K, Murray L, El-Omar E, Dickson A, El-Nujumi A, Wirz A, et al. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med 1998;339:1869-74. 42. Bruley Des Varannes S, Flejou JF, Colin R, Zaim M, Meunier A, Bidaut-Mazel C. There are some benefits from eradicating Helicobacter pylori in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther 2001;15:1177-85. 43. Danesh J, Lawrence M, Murphy M, Roberts S, Collins R. Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia. Arch Intern Med 2000;160:1192-8. 44. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia. A meta-analysis of randomized, controlled trials. Ann Intern Med 2001;134:3619. 45. Laheij RJ, Jansen JB, van de Lisdonk EH, Severens JL, Verbeek AL. Review article: symptom improvement through eradication of Helicobacter pylori in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther 1996;10:843-50. 46. Laheij RJ, van Rossum LG, Verbeek AL, Jansen JB. Helicobacter pylori infection treatment of nonulcer dyspepsia: an analysis of meta-analyses. J Clin Gastroenterol 2003;36:315-20. 47. Moayyedi P, Soo S, Deeks J, Forman D, Mason J, Innes M, et al. Systematic review and economic evaluation of Helicobacter pylori eradication treatment for non-ulcer dyspepsia. Dyspepsia Review Group. Br Med J 2000;321:659-64. 48. Jaakkimainen RL, Boyle E, Tudiver F. Is Helicobacter pylori associated with non-ulcer dyspepsia and will eradication improve symptoms? A meta-analysis. Br Med J 1999;319:1040-4. 49. Moayyedi P, Soo S, Deeks J, Delaney B, Harris A, Innes M, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev 2005;(1):CD002096.
Correspondence to: Dr Ahuja, Associate Professor. Fax: (11) 2658 8663. E-mail: vineetahuja2004@yahoo.com

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